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INFECTION AND IMMUNITY Michael Parkhouse Principal Investigator PhD in Biochemistry, University of London Head Immunology, Institute Animal Health, Pirbright, UK Director, Centro Nacional de Biotechnologia, Madrid, Spain Special Appointment-equivalent to University Professor, National Institute for Medical Research, Mill Hill, London Principal Investigator at the IGC since 2000 The theme of the group is the reciprocal adaptation between an infectious organism and its host. The necessity to recognise and destroy invading pathogens has played a crucial role in the evolution of the immune system of both vertebrates and invertebrates. At the same time, pathogens, in particular viruses, have evolved strategies to manipulate the immune system. An efficient immune system must select the immune effector mechanism most appropriate to the biology of the pathogen. Thus, the study of how pathogens control immune responses will offer novel approaches for the manipulation of the immune responses in health and disease, with novel vaccines and strategies to downregulate the immune system (e.g. inflammation) being the most obvious possibilities. Therefore, we are identifying and characterising virus host evasion genes directed towards subversion of cell biology and innate immunity. The two viruses that we have selected are Herpesvirus and the African Swine Fever Virus. EVALUATING AND CONTROLLING THE RISK OF AFRICAN SWINE FEVER (ASF) IN THE EU The aim is to provide new tools and strategies for the control of ASF in Africa and reduce the risk of importation and/or spread of the disease in EU member states. GROUP MEMBERS Rute Nascimento (Post-doc, started in July ) Sílvia Correia (Post-doc) Helena Costa (PhD student) Sónia Ventura (PhD student) Emanuel Costa (Research Technician) COLLABORATORS Sun Huaichang (College of Veterinary Medicine, Yangzhou University, China) Alexandre Leitão (Faculdade de Medicina Veterinária, Universidade Técnica de Lisboa, Portugal) John Sinclair (University of Cambridge, UK) Steve Goodbourn (St. George's Hospital, University of London, UK) FUNDING Framework Programme 7 (FP7), European Commission Fundação para a Ciência e a Tecnologia (FCT), Portugal We produced B602L, p54, A104R and K205R recombinant proteins which have been used as antigens to field test ASFV isolates in new recombinant ELISAs by Dr Carmina Gallardo, CISA-INIA. As the K205R protein revealed high IgM titres, it has been produced and sent to Dr Carmen Vela, INGENASA, to develop a new commercial kit able to detect recently ASFV infected animals. An additional ASFV Interferon evasion gene has been identified using luciferase reporter assays. INHIBITION OF THE RESPONSE OF THE AFRICAN SWINE FEVER VIRUS AGAINST HOST INTERFERON Our objective is to determine the mechanisms and consequences of three nonhomologous host evasion genes (I329L, K205R and A276R) of the economically important, frequently fatal African Swine Fever Virus (ASFV). All three genes inhibit a major component of innate immunity, the Interferon (IFN) response, and may have practical application through the development of novel pharmaceuticals that manipulate IFN responses and through the construction of an attenuated gene deletion ASFV vaccine. We identified the I329L gene as an inhibitor of TLR3 signalling pathway through targeting of TRIF (Ventura et al. 2012, in prep). The K205R gene was identified as an interacting partner of STAT2, therefore inhibits the host antiviral response by inhibiting the expression of interferon stimulating genes (ISGs) (Correia et al 2012, in prep). Definition of their cellular targets and impact on cellular processes is a necessary step prior to the construction of a deletion mutant virus vaccine. MECHANISM AND CONSEQUENCES OF AN IL-8 INDUCING HERPESVIRUS GENE The project builds on our own observations and experience with UL76 gene from Human Cytomegalovirus (HCMV), a novel virus host evasion gene previously lacking a function and, with the exception of the herpesviruses, still without any homologue in the database. The main objective of this project is to define the mechanisms employed by UL76 to induce IL-8 expression and G2/M cell cycle arrest. Understanding this virus strategy for manipulating cell division and stimulating IL-8 expression may be exploitable for the rational control of these important infections in humans, for example, the construction of attenuated herpes virus vaccines, and the development of possible novel approaches for the manipulation of host cell biology in health and disease. We demonstrated that UL76 induces IL-8 expression through NF-kB activation using deletion mutants of IL-8 promoter luciferase reporter. The activation of NF-kB by UL76 is dependent of IKK-beta and the degradation of IKB-alpha proteins. Moreover, expression of UL76 results in p65 translocation to the nucleus and in increased binding of p65 to the IL-8 promoter region as shown by chromatin immunoprecipitation. IGC ANNUAL REPORT ‘11 RESEARCH GROUPS 54
DISEASE GENETICS Carlos Penha Gonçalves Principal Investigator PhD in Immunology, University of Umea, 1999 Full Professor, Universidade de Lisboa, Portugal Head of Genomics Unit Principal Investigator at the IGC since 2005 Our scientific interests are concerned with the genetic basis of resistance/susceptibility to disease with special focus on malaria and diabetes. We aim to develop research programmes based on the systematic analysis of individual genetic factors involved in disease resistance/susceptibility, both in humans and in mouse models. Two diseases are the focus of our work: malaria and type-1 diabetes (T1D). We aim to investigate the pathogenesis of these diseases by combining cell and molecular biology methodologies with classical genetics techniques. In coming years a strong theme in the lab will be deciphering the role of particular cell types of the innate immune system in: 1. Mediating pathogen-induced pathology (in pregnancy and cerebral malaria); 2. Conferring infection resistance (in malaria liver stage); 3. Shaping the responsiveness to auto-antigens (in T1D). PREGNANCY-ASSOCIATED MALARIA Pregnancy-associated malaria (PAM) is a severe clinical complication of P. falciparum infection threatening the life of the mother and the foetus. Infected red blood cells (iRBC) adhesion and sequestration in the placenta are the inaugural events in placental malaria pathology but key investigations on the pathogenesis mechanisms are not amenable in human placenta. We developed two mouse models of PAM using Plasmodium berghei ANKA infected BALB/c females enabling us to follow several lines of investigations: GROUP MEMBERS Luciana Moraes (Post-doc) Nadia Duarte (Post-doc) Ligia Deus (PhD student) Joana Corte-Real (PhD student, left in December) Joana Rodo (PhD student) Lurdes Duarte (PhD student) Elizabeth Ball (PhD student) COLLABORATORS Lars Hviid (University of Copenhagen, Denmark) Chris Jansen (Leiden University Medical Center, Netherlands) Claúdio Marinho (Universidade de São Paulo, Brazil) Maria Mota (Instituto de Medicina Molecular, Portugal) Jon Clardy (Harvard Medical School, USA) Peter Crompton (National Institute of Health, USA) Taane Clark (London School of Hygiene and Tropical Medicine, UK) Rosário Sambo (Hospital Pediátrico de Luanda, Angola) Maria Jesus Trovoada (Centro Nacional de Endemias, S. Tomé e Príncipe) Dan Holmberg (University of Conpenhagen, Denmark) Linda Wicker (University of Cambridge, UK) FUNDING Fundação para a Ciência e a Tecnologia (FCT), Portugal Calouste Gulbenkian Foundation, Portugal • We use confocal and two-photon intra-vital microscopy techniques to measure the dynamics of increased adhesion of PAM parasite to the placenta tissue, in vivo; • We are testing the hypothesis that PM is not driven by a systemic condition but is rather a heterogeneous and localised inflammatory process. We propose that locally-acting immuno-mediators provided by the foetal tissues would have a crucial role in recruiting cellular components to the inflammatory infiltrate. Two manuscripts summarise the results obtained in 2011: Intravital placenta imaging reveals microcirculatory impact on sequestration dynamics and phagocytosis of Plasmodium-infected erythrocytes (Submitted). Distinct placental malaria patterns caused by Plasmodium berghei-derived strains that fail to induce cerebral malaria in the C57Bl/6 mouse (Submitted). PLASMODIUM DEVELOPMENT IN HEPATOCYTES The Plasmodium liver stage is an appealing target for the development of strategies to control malaria infection and has been a source of promising candidate vaccines. During malaria liver stage infection single parasites infect individual hepatocytes and develop into thousands of merozoites. This developmental process is largely asymptomatic and not amenable to study in humans, therefore malaria mouse models are instrumental in revealing parasite and host factors involved in the establishment of the liver stage infection. We propose to investigate mouse genetic models where we found alterations of liver parasite expansion with the aim of identifying host factors that hinder the regulation and efficiency of Plasmodium development in the liver. For this purpose we will use an exclusive tool set that includes a significant collection of relevant mouse strains and parasite mutants as well as our established expertise on mouse primary hepatocyte cultures and imaging techniques. IGC ANNUAL REPORT ‘11 RESEARCH GROUPS 55
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The Instituto Gulbenkian de Ciênci
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Page 19 and 20: MEIOSIS AND DEVELOPMENT Vítor Barb
Page 21 and 22: EPIGENETICS AND SOMA Vasco M. Barre
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Page 25 and 26: as a manuscript submitted in 2011 (
Page 27 and 28: We have found a new precursor struc
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Page 33 and 34: NEUROBIOLOGY OF ACTION Rui M. Costa
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Page 43 and 44: ACTIN DYNAMICS Florence Janody Prin
Page 45 and 46: EPIGENETIC MECHANISMS Lars Jansen P
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Page 49 and 50: PATTERNING AND MORPHOGENESIS Moisé
Page 51 and 52: EARLY FLY DEVELOPMENT Rui Gonçalo
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Page 57 and 58: COMPUTATIONAL GENOMICS José Pereir
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Page 71 and 72: PLANT GENOMICS Jörg Becker Researc
Page 73 and 74: NETWORK MODELLING Claudine Chaouiya
Page 75 and 76: NEURONAL STRUCTURE AND FUNCTION Inb
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Page 81 and 82: IMMUNE REGULATION Carlos E. Tadokor
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Page 85 and 86: ANIMAL FACILITIES Jocelyne Demengeo
Page 87 and 88: TRANSGENICS UNIT Moisés Mallo Head
Page 89 and 90: CELL IMAGING UNIT José Feijó Head
Page 91 and 92: GENOMICS UNIT Carlos Penha Gonçalv
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Page 95 and 96: ION DYNAMICS FACILITY Ana Catarina
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NATIONAL AND INTERNATIONAL RESEARCH
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PUBLICATIONS IGC ANNUAL REPORT ‘1
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IGC ANNUAL REPORT ‘11 PUBLICATION
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António Coutinho Professional Meri
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GRADUATE TRAINING AND EDUCATION
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Cells to organisms I 24 - 28 Octobe
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INDP - INTERNATIONAL NEUROSCIENCE D
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Extroduction 30 May - 3 June Organi
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PROGRAMME FOR ADVANCED MEDICAL RESE
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GTPB - THE GULBENKIAN TRAINING PROG
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THESES MSc THESES Sofia Pereira Dev
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SEMINARS AT THE IGC JANUARY 2011 DA
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MARCH 2011 DATE SPEAKER AFFILIATION
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On the origin and diversification o
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HELENA COSTA Mechanism of IL-8 indu
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Of models and mechanisms of ion dyn
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The centromere: A showcase for epig
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Mechanisms determining adult body s
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The evolutionary dynamics of (Rab)
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HENRIQUE TEÓTONIO The genetic basi
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EMBnet - ANNUAL GENERAL MEETING 201
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PUBLIC ENGAGEMENT IN SCIENCE
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Science Projects Support Programme
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FUNDRAISING Maria João Leão Head
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PARTNERS AND SPONSORS Several partn
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